Sustained release capsules

ABSTRACT

The invention relates to an intraruminal sustained release capsule which is capable of delivering a sustained release dose of a first medicament to an animal, as well as either or both of a dump dose of a second medicament or mineral, and an exit dose of a third medicament or mineral. The capsule can have a dissolvable overcap moulded from plasticised starch enabling a dump dose of medicament to be held between the overcap and one end of the capsule. A piston within the body of the capsule can be modified to enable it to accommodate an exit dose of medicament within its hollow interior which is aligned with an aperture at the end of the capsule which enables release of the medicaments to the rumen. After insertion of the capsule in the animal the overcap (if present) dissolves and separates from the capsule to release the dump dose of medicament. The sustained release medicament is then dispensed via the apertured end, followed by the release of the exit dose of medicament (if present).

FIELD OF THE INVENTION

This invention relates to an intraruminal device, and more particularlyto an intraruminal sustained release capsule designed to release two ormore active ingredients into the rumen of a ruminant animal, such as asheep, cow, goat, deer etc.

BACKGROUND OF THE INVENTION

There are a number of intraruminal devices and sustained releasecapsules and formulations presently available. In general the devicescurrently available are in the form of a capsule, which comprises: asubstantially hollow tubular body, which is sealed at one end by a cap,and partially sealed at the second end by an annular flange, whichdefines an opening. There is provision within the body for the inclusionof a solid therapeutic composition.

Many of the currently available intraruminal devices contain a springand plunger mechanism for urging the solid therapeutic compositiontowards the opening. The cap end may also have attached to it aplurality of resilient arms designed to prevent regurgitation of thedevice by the animal.

Intraruminal devices are inserted through the oesophagus into theanimal's rumen. Once in the rumen they commence the release of thetherapeutic composition over a prolonged period of time. A number ofsuch formulations are available which are all capable of releasing asingle therapeutic drug, such as an anthelmintic, and in some cases arange of supplementary trace elements.

Sustained release capsules have been available for over fifteen years.These devices release active ingredients or trace elements into therumen of an animal for a period of 90-180 days.

There are two main types of sustained released capsule:

Simple Erodible Systems

These were the first type of sustained release device introduced to themarket. They are generally of a waxy or metallic construction and are inthe shape of a simple cylinder. Erosion either occurs from over theentire surface of the device, or in some cases the device may have beendipped in a coating material so that only the ends of the device areexposed. In this case payout will be able to be controlled moreeffectively. The interaction with the rumen contents (amount of grassand liquid content) determines the rate of erosion of the device.

Examples of such devices include:

Alltrace Mineral Bolus (Agrimin, UK)—This is an erodible boluscontaining: Copper (16,379 mg), Cobalt (236 mg), Selenium (251 mg),Manganese (8,326 mg), Zinc (13,382 mg), Iodine (497 mg), Vitamin A(549,408 i.u.), Vitamin D (3109,881 i.u.) and Vitamin E (1,099 i.u.).Two boluses are administered to each animal weighing 150 kgs or more,with the payout period being 240 days. To retain the bolus in the rumenthe device has a sold metal densifier element which erodes after thelighter mineral elements have dissolved. The advantage of the device isthe high loading of active ingredients and the fact that the device willfully erode leaving no part retained in the animal. Disadvantage of thisstyle of erodible bolus is that it is not possible to achieve a linearrelease rate.Optimag Magnesium Bolus (Norbrook, UK)—A solid metallic bolus containing100 g of magnesium released over approximately 4 weeks. These are usedin adult cattle as an aid to maintenance of magnesium intake.

In both of the above cases the aim of bolus administration is tomaintain mineral levels in the treated animal for a prolonged period oftime. Neither device allows for complex payout profiles as might berequired if the farmer wished to deliver an immediate short-acting doseof a particular active ingredient to be followed by the sustained payoutof the minerals in question.

Sustained-Release Devices

A relatively new technology is the category of sustained-releasedevices. In general these are in the form of a plastic capsule,comprising: a substantially hollow tubular body, which is completelysealed at one end by a cap, and partially sealed at the second end by anannular flange, which defines an opening. There is provision within thebody for the inclusion of a solid therapeutic composition.

Many of the currently available sustained release devices contain aspring and plunger mechanism for urging the solid therapeuticcomposition (either in the form of solid wax or stack of tablets)towards the opening. Other devices rely on osmotic pressure to expand adriver portion in the base of the capsule. This driver portion causesthe active contents to be expelled from the open end of the capsule. Thediameter of the opening can be used to increase or restrict the speed ofpayout of the device.

The capsule may be retained in the rumen of the animal either by aplurality of resilient arms protruding from the cap end of the device,or by a weighted metal densifier element within the body of the device.

Typically this style of device is used to deliver active ingredientsrequiring a greater precision of payout such as anthelmintics. In thesecases the daily dose of anthelmintic is low compared to the amountrecommended in a standard oral dose.

Examples of sustained release devices include:

IVOMEC SR Bolus (MSD Agvet)—Containing 1.72 g ivermectin releasing over140 days. This device uses osmotic pressure to expand a driver portionin the base of the capsule. The expansion of this driver portion urgesthe solid wax formulation containing ivermectin towards the opening.EXTENDER SeCo (Merial)—Containing 4.62 g albendazole releasing over 100days, and IVOMEC Maximizer Capsule (Merial)—Containing 160 mg ivermectinreleasing over 100 days. Both of these devices utilise a spring portionto urge a stack of tablets containing the active ingredients towards theopening. At the opening the face of the exposed tablet forms a gel whichis released into the rumen.

There are times however when even sustained release of one or moresubstances over a prolonged period is insufficient to satisfy animalhealth needs. In certain cases the farmer may wish to deliver anadditional substance in an immediate or dump release fashion prior to orfollowing the period of sustained release.

Examples of such cases could include:

When a secondary trace element or mineral treatment is required to begiven to an animal at the same time as a sustained release treatment ofan anthelmintic. Traditionally this would mean that the farmer wouldadminister a separate treatment in the form of a liquid drench or oralcapsule. An example of this is that farmers will often give a copperoxide needle treatment in the form of a gelatine capsule for preventingcopper deficiency. It can be recognised that this separate treatment istime consuming and inconvenient.

A further example is that the manufacturers of EXTENDER SeCo recommendthat a large “primer” or initial dose of an effective oral anthelminticis given at the same time as the capsule is inserted into the animal.The purpose of this primer dose is to control the adult stage parasitesthat are resident in the animal. Once this is done the capsule will beable to effectively control any new incoming larvae for the effectivepayout period of the device.

Another example is that there is a concern that some single activesustained release anthelmintic devices may not effectively control allparasites for the full duration of the payout period. In some cases itmay be desirable to administer to the animal what is known as an “exit”dose. This is a large dose of anthelmintic administered at a single timepoint sufficient to control adult parasites that may have survived thesmaller sustained dose of anthelmintic.

Recently there have been attempts to incorporate priming and/or exitdoses into sustained release capsules so that there is no need for thefarmer to administer a separate treatment.

These are typically made by incorporating one or more fast releasingtablets into the stack of sustained release tablets contained within thedevice. These fast release tablets contain disintegrants andeffervescent materials. Unfortunately the fast release of the tablet canallow moisture to seep through the annular flange defining the openingand down the inside of the capsule body. This can then impede release ofsubsequent sustained release tablets.

OBJECT OF THE INVENTION

It is an object of the present invention to provide an improvedintraruminal device and/or an improved sustained release capsule or onewhich will at least provide the public with a useful choice.

STATEMENT OF INVENTION

In a first aspect the invention provides a sustained release capsulecomprising a hollow tubular body sealed at a first end, a movable pistonwithin the body, a spring biasing the piston towards a second end of thebody, an apertured cover at the second end to define a first chamberbetween the movable piston and the apertured cover capable of containinga first dose of material within the hollow tubular body for subsequentsustained release through the apertured cover into the rumen of ananimal, wherein an overcap is releasably attached to the device at oneend thereof to form a void between an end of the device and the overcapcapable of containing a second dose of material within the void so thatin use the second dose of material is delivered to the rumen when theovercap is breached or detaches from the device.

Preferably the overcap is attached to the second end of the device toform a void between the apertured cover and the overcap capable ofcontaining the second dose of material within the void so that in usethe second dose of material is delivered to the rumen when the overcapis breached or detaches from the second end.

Preferably the overcap is releasably attached to the capsule by adissolvable attachment.

Preferably the overcap is made of a material which will dissolve orbreakup in the rumen.

Preferably the overcap is made of a material selected from the groupcomprising cellulosic fibre, cardboard, paper, a water soluble plasticsmaterial, and starch.

Preferably the body has at least one external protrusion adapted in useto assist in retaining the capsule in the rumen of an animal.

Preferably the at least one protrusion consists of a pair of foldablewings.

Preferably the capsule is loaded with a first dose of material.

Preferably the capsule is loaded with a second dose of material in theovercap.

Preferably the second dose of material in the overcap comprises copperneedles.

Alternatively this material in the overcap may comprise one or moreanthelmintics.

In a second aspect the invention provides a sustained release capsulecomprising a hollow tubular body sealed at a first end, a movable pistonwithin the body, a spring biasing the piston towards a second end of thebody, an apertured cover at the second end to define a first chamberbetween the movable piston and the apertured cover capable of containinga first dose of material within the hollow tubular body for subsequentsustained release through the apertured cover into the rumen of ananimal, wherein an overcap is releasably attached to the second end toform a void between the apertured cover and the overcap capable ofcontaining a second dose of material within the void so that in use thesecond dose of material is delivered to the rumen when the overcap isbreached or detaches from the second end.

Preferably the overcap is releasably attached to the second end by adissolvable attachment.

Preferably the overcap is made of a material which will dissolve orbreakup in the rumen.

Preferably the overcap is made of a material selected from the groupcomprising cellulosic fibre, cardboard, paper, a water soluble plasticsmaterial, and starch.

Preferably the body has at least one external protrusion adapted in useto assist in retaining the capsule in the rumen of an animal.

Preferably the at least one protrusion consists of a pair of foldablewings.

Preferably the capsule is loaded with a first dose of material.

Preferably the capsule is loaded with a second dose of material in theovercap.

Preferably the second dose of material in the overcap comprises copperneedles.

Alternatively this material in the overcap may comprise one or moreanthelmintics.

In a third aspect the invention provides a sustained release capsulecomprising a hollow tubular body sealed at a first end, a movable pistonwithin the body, a spring biasing the piston towards a second end of thebody, an apertured cover at the second end to define a first chamberbetween the movable piston and the apertured cover capable of containinga first dose of material within the hollow tubular body for subsequentsustained release through the apertured cover into the rumen of ananimal, wherein the movable piston has an end face facing towards thefirst dose, a hollow central sleeve extending rearwardly from the endface to assist in locating a spring, an aperture in the end face intothe hollow interior of the central sleeve, the central sleeve having aclosed portion distal from the end face to create a void capable ofcontaining an exit dose of material.

Preferably the piston further includes an optional outer sleeveseparated from the central sleeve to create an annular void capable ofcontaining the spring.

Preferably the sustained release capsule further includes an overcapwhich is releasably attached to the second end to form a void betweenthe apertured cover and the overcap capable of containing a second doseof material within the void so that in use the second dose of materialis delivered to the rumen when the overcap is breached or detaches fromthe second end.

Preferably the overcap is releasably attached to the second end of thecapsule by a dissolvable attachment.

Preferably the overcap is made of a material which will dissolve orbreakup in the rumen.

Preferably the overcap is made of a material selected from the groupcomprising cellulosic fibre, cardboard, paper, a water soluble plasticsmaterial and starch.

Preferably the body has at least one external protrusion adapted in useto assist in retaining the capsule in the rumen of an animal.

Preferably at least one protrusion consists of a pair of foldable wings.

Preferably the capsule is loaded with a first dose of material.

Preferably the capsule is loaded with a second dose of material in theovercap.

Preferably the capsule is loaded with an exit dose of material.

Preferably the second dose of material in the overcap comprises copperneedles.

Alternatively this material in the overcap may comprise one or moreanthelmintics.

Preferably the sustained release capsule contains a dump dose ofmaterial within the overcap, a sustained release dose of material withinthe body of the capsule and an exit dose of material within the piston.

In a fourth aspect the invention provides a sustained release capsulecomprising a hollow tubular body sealed at a first end, a movable pistonwithin the body, a spring biasing the piston towards a second end of thebody, an apertured cover at the second end to define a first chamberbetween the movable piston and the apertured cover capable of containinga first dose of material within the hollow tubular body for subsequentsustained release through the apertured cover into the rumen of ananimal, wherein the movable piston has an end face facing towards thefirst dose, a hollow central sleeve extending rearwardly from the endface to assist in locating a spring, an aperture in the end face intothe hollow interior of the central sleeve, the central sleeve having aclosed portion distal from the end face to create a void capable ofcontaining an exit dose of material, and wherein an overcap isreleasably attached to the device at one end thereof to form a voidbetween an end of the device and the overcap capable of containing asecond dose of material within the void so that in use the second doseof material is delivered to the rumen when the overcap is breached ordetaches from the device.

Preferably the piston further includes an optional outer sleeveseparated from the central sleeve to create an annular void capable ofcontaining the spring.

Preferably the overcap is attached to the second end of the device toform a void between the apertured cover and the overcap capable ofcontaining the second dose of material within the void so that in usethe second dose of material is delivered to the rumen when the overcapis breached or detaches from the second end.

Preferably the overcap is releasably attached to the capsule by adissolvable attachment.

Preferably the overcap is made of a material which will dissolve orbreakup in the rumen.

Preferably the overcap is made of a material selected from the groupcomprising cellulosic fibre, cardboard, paper, a water soluble plasticsmaterial, and starch.

Preferably the body has at least one external protrusion adapted in useto assist in retaining the capsule in the rumen of an animal.

Preferably the at least one protrusion consists of a pair of foldablewings.

Preferably the capsule is loaded with a first dose of material.

Preferably the capsule is loaded with a second dose of material in theovercap.

Preferably the capsule is loaded with an exit dose of material.

Preferably the second dose of material in the overcap comprises copperneedles.

Alternatively this material in the overcap may comprise one or moreanthelmintics.

Preferably the sustained release capsule contains a dump dose ofmaterial within the overcap, a sustained release dose of material withinthe body of the capsule and an exit dose of material within the piston.

DRAWINGS

These and other aspects of this invention, which should be considered inall its novel aspects, will become apparent from the followingdescription, which is given by way of example only, with reference tothe accompanying drawings, in which:

FIG. 1 is a side elevation of a first embodiment of the inventioncapable of providing a dump dose of material.

FIG. 2 is a cross-sectional view on lines A-A through the capsule bodyof FIG. 1.

FIG. 3 is an enlarged sectional view of the overcap of FIG. 1.

FIG. 4 shows a side elevation of a second embodiment of the inventioncapable of providing a dump dose of material.

FIG. 5 is a cross-sectional view on lines A-A through the capsule bodyof FIG. 4.

FIG. 6A is an enlarged sectional view of the overcap of FIG. 4.

FIG. 6B is a further enlarged sectional view of part of the overcap ofFIG. 6A.

FIG. 7 shows a side elevation of the second embodiment of the inventionshowing a dump dose tablet contained within the overcap.

FIG. 8 is an end elevation of a third embodiment of the inventioncapable of providing an exit dose of material.

FIG. 9 shows a cross-sectional view of the exit dose embodiment of FIG.8.

FIG. 10 shows an enlarged side elevation of a piston for insertion inthe capsule.

FIG. 11 is an end elevation of the piston of FIG. 10.

FIG. 12 shows a cross-sectional view of the piston of FIG. 10.

FIG. 13 shows a similar cross-sectional view to that of FIG. 9 but thistime fully loaded with tablets between the piston and the aperturedcover (before dispensing commences) and an exit dose loaded within thecavity of the central sleeve of the piston.

FIG. 14 shows a cross-sectional view of the capsule of FIG. 13 after thesustained released tablets have been dispensed and the piston is fullyextended so that the exit dose can be dispensed via the aperture in thecover.

FIG. 15 shows a cross sectional view of a capsule described in example 4with the wings folded. This capsule combines both the dump dose and theexit dose arrangements.

FIG. 16 is a cross sectional view of the capsule of FIG. 15 but with thewings extended.

DESCRIPTION OF DRAWINGS

The following description will describe the invention in relation topreferred embodiments of the invention, namely a sustained releasecapsule.

The invention is in no way limited to these preferred embodiments asthey are purely to exemplify the invention only and it should beunderstood that possible variations and modifications which would bereadily apparent are intended to be included without departing from thescope of the invention.

There are two aspects to the current invention. The first aspectaddresses the need to provide a priming dose capability for a sustainedrelease capsule, while the second aspect addresses the need to providethe exit dose capability.

Priming Dose

The first preferred embodiments of this invention are designed toachieve an outcome whereby a secondary treatment formulation can bemounted with the sustained release device without requiringmodifications to the geometry of the device that would impede subsequentpayout from the sustained release portion. This is achieved by holdingthe secondary treatment, which could be in the form of a liquid, powder,fine particles or tablets under a releasable or detachable overcapmounted on one end of the device. This overcap is able to be constructedof moulded fibre, cardboard or preferably a biodegradable starchmaterial and would serve the purpose of protecting the secondarytreatment during storage and transport.

Because the overcap would rapidly detach from the capsule once it was inthe rumen it would leave the basic geometry of the sustained releasecapsule unchanged. Preferably the release of the overcap results fromthe rumen fluid causing the material of the cap to dissolve and/orbiodegrade. However, in other embodiments of the invention the overcapcan be made of a material that is more durable and is attached to thecapsule by a soluble tape or the like, such that the release of theovercap results from the rumen fluid causing the soluble tape todissolve and/or biodegrade. In this case the more durable material islikely to be made of a material which will eventually biodegrade insidethe animal even if it biodegrades at a slower rate than the solubletape.

Example 1

FIGS. 1-3 of the attached drawings provide an example of a firstembodiment of the invention, which is capable of providing a dump doseof material to the rumen of a ruminant animal. In this embodiment of theinvention, an overcap, preferably made of a starch material is mountedon the end of the main capsule device.

The capsule 100 is shown in side elevation in FIG. 1. The capsule 100has foldable wings 101 which when extended protrude at right angles tothe page. The extended wings are shown in cross sectional view in FIG.2, cross section being taken on lines AA of FIG. 1. The capsule 100 hasan overcap 110 mounted on one end.

The capsule 100 and foldable wings 101 may be of a generallyconventional construction having a moveable piston inside the body ofthe capsule 100, and as shown in FIG. 2 this is at or adjacent theclosed end 103, the moveable piston 105 having a closed end face whichpushes against a stack of tablets or other medicament (not shown)contained in the void 102 within the capsule 100. The other end of thecapsule 100 has a closed end 104 having a central aperture 107. This isshown in more detail in the enlarged view of the overcap shown in FIG.3. In this view, the closed end 104 is shown attached to the body of thecapsule by means of a screw thread or clip on attachment 108, which alsohas a sealing rib 109 beyond the end of the screw thread 108. There isalso a sealing lip 106 which mates with a groove in the end of thecapsule body, to prevent leakage of rumen fluid into the body of thecapsule other than via aperture 107, and conversely prevent the leakageof medicament around the edge of the end face 104.

With the exception of the overcap 110 and its attachment to the capsule100, the other components of the capsule device 100, 101, 102, 103, 104,and 105 can be of conventional sustained release capsule construction.

In this embodiment of the invention the novel feature is the provisionof an overcap 110, which is preferably made of a mouldable starchmaterial, and which is of a sufficient shape and size so as to fitsnugly over the end face 104 of the capsule, and clip over the sealingrib 109. Thus the diameter of the overcap 110 is only slightly greaterthan the diameter of the capsule body 100. The overcap 110 preferablyhas a rounded nose and rounded end, so as not to provide any obstructionor discomfort when the device is swallowed by the animal being treated.

The moulded overcap 110 is of such a size and shape so as to provide avoid 120 between the closed end 104 of the capsule and the inside edgesof the overcap, the void being for the inclusion of a dump dose of amedicament. The medicament might be in the form of a speciallyformulated tablet which is designed for rapid release in the rumen oncethe overcap has been dissolved or detached or otherwise breached by therumen fluid, or it might be a collection of copper oxide needles orparticles, or any other dose which is to be administered to the animalprior to the release of the sustained release pay load contained withinthe void 102 in the body of the capsule. In some cases the dump dosemedicament might be a fast acting anthelmintic, to flush out any adultparasites, whilst the medicament in the sustained release portion of thedevice consists of a long acting anthelmintic designed to treat theimmature and juvenile parasites. Of course many other combinations arepossible.

Prior to administration of the capsule, the wings 101 will be foldeddown and attached to the sides of the capsule 100. As shown in FIG. 2the wings 101 may be of a length such that they extend slightly over theovercap, and thus the ends of the wings 101 may be narrowed or taperedin order to fit snugly against the end of the overcap when they arefolded down. The wings 101 can be then secured to the body of thecapsule or the overcap by suitable quick release means, typically awater soluble or dissolvable tape, which will degrade quickly once thecapsule has been inserted into the rumen, thereby releasing the wings sothey extend into the protruding position as shown in FIG. 2 in order toprevent regurgitation of the capsule by the animal being treated.

By modifying the properties of the starch the overcap 110 can bedissolved by the rumen fluid, and depending upon the size and thicknessof the overcap, the overcap will then start to jellify, and detach fromthe body of the capsule 100. In the most preferred form of theinvention, the overcap 110 is designed to detach from the body of thecapsule, as the wall thickness of the overcap is thinner adjacent thescrew threaded portion 108 of the end portion of the capsule. However itis possible that the overcap could be designed to be breached in otherportions or areas before actually detaching, so that the dump dose ofmedicament can be quickly released into the rumen even if the overcaphas not itself been detached from the capsule body.

Once the dump dose of medicament has been released either by the capdetaching, or the cap being breached, rumen fluid can then enter theaperture 107 of the capsule body, and the sustained release payloadcontained in the void 102 will start being dispensed as it is dissolvedby the rumen fluid. During this time the moveable piston 105 is biasedtowards the stack of tablets or capsules or other medicament containedwithin the void 102, and as the medicament dissolves the piston movestowards the closed end 104 of the capsule.

Example 2

FIGS. 4-7 of the attached drawings provide an example of a secondembodiment of the invention, which is capable of providing a dump doseof material to the rumen of a ruminant animal. In this embodiment of theinvention, an overcap, preferably made of a starch material is retainedon the inside of a lip on the end of the main capsule device.

The capsule 200 is shown in side elevation in FIG. 4. Again, the capsule200 has foldable wings 201 which extend as shown in the cross sectionalview in FIG. 5, cross section being taken on lines A-A of FIG. 4. Thecapsule 200 has an overcap 230 mounted on one end. The capsule has wings201 and a moveable piston 205 in a similar arrangement to that of thefirst embodiment described in example 1. The difference between thesetwo embodiments of the invention is shown in more detail in FIGS. 6A and6B. The closed end 204 of the capsule having the central aperture 207now extends rearwardly to form a rearwardly extending sleeve 210 havingan inwardly facing circumferential lip 211. The overcap 220 has anoutwardly facing circumferential protrusion 221 designed to fit underthe lip 211, in order to attach the overcap to the capsule. The overcap220 is preferably made of a hollow moulded starch material, therebydefining a void 230. The void 230 is designed to contain a dump dose ofa medicament.

FIG. 7 shows a side view of the capsule which contains a dump dose of amedicament within the overcap in the form of a single tablet 240. Themedicament could however be in any desired form.

It is noted that in Examples 1 and 2 the overcap prevents any rumenfluid from entering the aperture 107 or 207 until the overcap has beendetached from the end of the capsule device, or until the overcap hasbeen breached and the dump dose of medicament has been released.

Preferred Materials

In the preferred embodiments of the invention, the overcap is madeentirely of an acceptable dissolvable material such as potato or cornstarch (e.g. Plastarch) or alternatively Polylactide acid (e.g.Cereplast Compostables material). Pure starch possesses thecharacteristic of being able to absorb moisture and is thus ideallysuited for this application. Flexibilisers and/or plasticisers such assorbitol and glycerine may be added to the starch so that the starch canbe injection molded into the desired shape.

Upon contact with the rumen fluids the overcap will begin to gellify andbecome detached from the capsule. Once the overcap is detached, the dumpdose of medicament located within or underneath the overcap is releasedinto the rumen.

The capsule 100 or 200 and wings 101 or 201 and end closure 104 or 204can all be moulded of a suitable plastics material.

Advantages of the Dump Dose Configurations

The use of the plasticised starch material for the overcap has asecondary and unexpected benefit in that it develops a slippery surfaceon contact with saliva/mouth moisture, which can aid passage of thecapsule down the oesophagus of the animal when treated.

The thickness of the walls of the overcap can be adjusted in order toalter the time taken to separate the overcap from the capsule device.

The fact that the overcap can become entirely separated from the capsulemeans that there is no interaction or interference with the dynamics ofrelease of the sustained release medicament from the body of thecapsule.

Variations of the Dump Dose Configurations Include:

Anthelmintic release devices—a primary dose of one or more activeingredients is formulated in one or more tablets. This dose is storedunder the overcap. The overcap is mounted at the opening end of thecapsule. Within the capsule body is a plurality of tablets or a stack oftablets containing a sustained release formulation of one or moreanthelmintics.Mineralised capsules—in which a primary dose of copper oxide wireparticles is stored under the overcap. Once again the overcap is mountedat the opening end of the capsule. Within the capsule body is aplurality of tablets or a stack of tablets containing a sustainedrelease formulation of one or more minerals such as selenium and cobalt.

It should be recognised that there are many combinations andpermutations of medicaments that are capable of being used with thisinvention. For example the overcap may contain any number of individualmaterials each having a different biological effect.

It is also possible that the overcap could be constructed of other typesof material such as cardboard or plastic. The overcap could be attachedto the capsule by means of a clip or alternatively by water solubleadhesive tape or some other non-permanent attaching means.

One such variation could be the use of an overcap made of cardboard orplastic which is secured to the end of the capsule body by means of thesame dissolvable tape used to hold the wings in place. In anotherversion the wings may well have a provision which clips into thecardboard or plastic overcap, and the wings are then held in place by adissolvable tape so that once the tape has been released, the movementof the wings will cause the plastic or cardboard overcap to be detachedfrom the dump dose body.

Although the preferred embodiments have been described with reference tothe overcap fitting over the closed end of the capsule, i.e. at the enddistant from the attachment of the wings, it will be appreciated thatthe overcap could be positioned at the same end of the capsule where thewings are attached.

In such an arrangement, the wings will be folded down prior toadministration of the capsule to the animal, in the position shown inFIG. 15, and taped in place. The overcap can then be fitted over the endof the capsule adjacent the hinge point of the wings, so that theovercap would sit over the folded wings. Taping of the overcap to thecapsule enfolded wings could also serve to hold the wings in place, oralternatively the moulded overcap could be designed to fit snugly overthe hinge point of the wings, and the wings held in place by a solubletape, such that when the soluble tape releases, the overcap would bedischarged from the capsule by the motion of the wings as they move outto the extended position shown in FIG. 16.

Although such a modified overcap and its dump dose payload would be ableto be released into the rumen shortly after the insertion of the capsuleinto the animal, this arrangement is less advantageous, in that theovercap no longer covers the aperture leading to the sustained releasepayload. This means that the sustained release payload may start to bereleased possibly before the overcap is released from the capsule. Thusit will be appreciated that having the overcap 410 on the end of thecapsule as shown in FIGS. 15 and 16 distant from the anchor point of thewings 401, there is a clear distinction between release of the dump doseof medicament before the commencement of the release of the sustainedrelease dose of medicament, and before the release of the exit dose ofmedicament. However there may be some cases where the provision of adump dose at the wing end of the capsule may be advantageous, and theremay be some cases where it is desirable to have a dump dose at both endsof the capsule, one at the anchor point of the wings and one at theother end of the capsule distant from the anchor point of the wings.

Many other variations are possible.

Exit Dose

It is also desirable for a sustained release capsule to include an exitdose that can be released at the conclusion of the sustained releasepayout period instead of, or as well as, the dump dose. If the capsuleis used to release a medicament such as an anthelmintic over a longperiod, the exit dose would preferably be in the form of a largerimmediate release of anthelmintic sufficient to kill any parasites thatmay have survived the low level of sustained release of anthelmintic.However there are practical problems with achieving this desiredembodiment.

Just as there are difficulties in providing for a priming dose withinthe body of the capsule the same basic problems are present whenincluding an exit dose. Because the fast release exit tablet must beconstructed of a more soluble formulation than the sustained releasetablets this can result in the release of the anthelmintic drug throughthe matrix of the sustained release medicament or tablet stack before itis meant to be released. There is also an additional problem of how tofit such an exit dose into the device when it is desired to include asmuch medicament or as many sustained release tablets into the capsule aspossible.

To address these issues, the next embodiment of the invention allows forthe inclusion of an exit dose of medicament in a modified pistoncovering the end of the spring within the capsule device. Currentsustained release capsules fitted with a spring have a flat faced piston(which serves as the spring cover). This cover contacts the face of thelast sustained release tablet within the tablet stack inside thecapsule. There is however a void space within the inner diameter of thespring behind the spring cover. This space is currently not utilised forany practical purpose.

Example 3

FIGS. 8-14 of the attached drawings provide an example of a thirdembodiment of the invention, which is capable of providing an exit doseof material to the rumen of a ruminant animal.

The capsule 300 is shown in side elevation in FIG. 9. The capsule 300has a pair of foldable wings 301, and an apertured 307 end face 304,generally of the type as described in examples 1 and 2. FIG. 8 shows arib 306 on the underside of the wings 301.

Inside the capsule device 300 there is a modified moveable piston,indicated generally at 305 of FIG. 9. This piston is modified in thesense that it no longer has a sealed end face, but has an aperture 315at the centre of the end face 320 which leads into a hollow chamber 316in which an exit dose of medicament can be stored. This hollow chamber316 forms the central sleeve 317 about which a coil spring (not shownuntil FIGS. 15 and 16) can be positioned and held in the outer sleeve318 and compressed between end face 320 and stop 322, so that the coilspring biases the medicament or tablet stack contained within the bodyof the device (as shown at 330 in FIG. 13) towards the exit end 304 ofthe device. The exit end face 304 is securely held in place by a screwthread 308 or the like as previously described, and has a centralaperture 307 which aligns with the central aperture 315 in the end face320 of the moveable piston.

The moveable piston 305 is shown in more detail in FIGS. 10 (in sideelevation), 11 (in end elevation) and 12 (in cross section).

FIG. 13 shows an embodiment of the capsule containing a stack of tablets330 in the main body of the capsule. The moveable piston 305 is locatedat the end of the capsule device where the wings are attached, and asthe tablets are sequentially dissolved by the rumen fluid enteringthrough the aperture 307 in the end face 304, the dissolved material isgradually forced out of the aperture in the end face by the moveablepiston 305 moving under the influence of the spring towards the end face304.

When the moveable piston 305 reaches the end face 304 as shown in FIG.14, it will be apparent that the aperture 307 in the end face is alignedwith the aperture 315 in the central chamber 316 of the moveable piston,and any material stored in chamber 316 as an exit dose, will then bereleased into the rumen. FIG. 13 shows an exit dose of medicament 331contained within the chamber 316.

Typically the exit dose 331 will be a fast release tablet, whichdissolves more quickly than the sustained release formulations of thepayload 330 in the body of the capsule, and hence the material of theexit dose will be released quickly into the rumen.

Because the exit dose 331 is stored within a chamber 316 in the modifiedpiston, it does not add to the length of the capsule, and this exit doseconfiguration can also work with the dump dose configuration of examples1 and 2.

Example 4

FIGS. 15 and 16 show a capsule generally indicated at 400 which combinesthe features of Examples 1 and 3, namely an external biodegradableovercap 410 containing an initial dump dose of medicament 440, and amodified piston 405 inside the capsule containing an exit dose ofmedicament 431.

Both FIGS. 15 and 16 are sectional views (similar to the sectional viewof FIG. 2 based on a similar section A-A) except that FIG. 15 shows thewings 401 folded prior to insertion of the capsule into an animal. Whenfully assembled with the wings 401 folded downwards as in FIG. 15, thewings can be held in place by a biodegradable attachment such as a tapemade from starch or other dissolvable material. FIG. 15 shows that thewings when folded do not touch the moulded overcap but that the wingsthemselves are of a thickness comparable to the wall thickness of theovercap so that the wings and moulded overcap provide a relativelysmooth exterior to the capsule to enable it to be swallowed by theanimal.

FIG. 15 shows the moulded overcap 410, preferably moulded from abiodegradable starch material, sitting over the end closure 404 of thecapsule, the end closure 404 having a central aperture 407 to allow thesubsequent release of the medicament inside the capsule after theovercap has been detached from the capsule body. Inside the capsule bodythere is a sequence of tablets 430 preferably containing a sustainedrelease composition or compositions so that the payload inside thecapsule can be released slowly over time as the rumen fluid entersthrough the aperture 407 and successively dissolves the material of eachtablet. Although it is preferred to use tablets, other dosage forms canbe used inside the body of the capsule. The tablet stack 430 shown inFIG. 15 is biased towards the exit aperture 407 by means of a coilspring 450 shown fitted within the recess of the piston 405. Asdescribed in Example 3, this piston has a central chamber 416 having anaperture 415 opening towards the tablet stack, which enables an exitdose of medicament to be positioned in this chamber. This chamber 416and its aperture 415 will eventually be able to access the aperture 407in the end closure 404 when all of the tablets have been dissolved andthe coil spring 450 has pushed the piston 405 towards the end closure404 of the capsule.

FIG. 16 shows the capsule containing a dump dose of medicament 440, asustained release tablet stack 430, and an exit dose of medicament 431,but with the wings 401 extended, as they would be shortly afterinsertion of the capsule into the rumen, and before the moulded overcap410 had been dissolved enough to be released from the end of the capsulebody.

Dimensions:

The device of FIGS. 15 and 16 shows the device printed on a scale of1:1. However the device can be made in many different sizes depending onthe size of the animal for which it is intended.

FIG. 15 shows a suitable sized device for cattle weighing from 100 to200 kg. The precise size and dimensions of the same sustained releasecapsule depend upon the size of the animal into which it is beinginserted. For example, the device may be produced in five differentsizes, a small unit for a weaner lamb, a slightly larger version foradult sheep, an intermediate version as shown in FIG. 15 for weanercattle from 100 to 200 kg in size, a larger size for larger weanercattle weighing from 200 to 300 kg, and a larger size for adult cattleweighing from 400 to 600 kg.

Of course many other variations are possible, and the size and inparticular the length of the device may depend upon the payload and thedesign time of the payout of the payload.

Advantages of the Exit Dose Configuration (Example 3 and the CombinedConfiguration of Example 4)

By designing the piston to include a well shaped portion projectingrearward from the face that contacts the last sustained release tablet,a suitable repository can be created to contain an exit dose ofmedicament.

The well shaped portion has an additional advantage to merely creating asuitable repository for the exit dose material. That is, it alsoconcentrates the exit dose material at the centre of the tablet stackwhere it is aligned with the aperture 407 once the capsule has paid outthe sustained release tablet stack portion 430. Because each tablet inthe sustained release tablet stack 430 tends to collapse and gellifyfrom the centre portion immediately adjacent the aperture 407 first,this makes it highly desirable that the exit dose medicament is alsoaligned with this point. This means that even if the last sustainedrelease tablet is not completely paid out the exit dose 431 will stillbe cleanly and effectively released.

Because the modified piston 405 does not impede significantly on theinterior volume of the capsule, it is still possible to provide asignificant sustained release payload 430 within the body of the capsuleand also provide for the provision of an exit dose 431 within the piston405. Thus the combined capsule of FIGS. 15 and 16, or other variationsof this combination concept, will not be unduly long in length, and yetwill still provide for the three different types of payload, that is,the dump dose of medicament, the sustained release dose of medicament,and the exit dose of medicament, all within the confines of such acapsule and overcap.

Variation of the Exit Dose Configuration

Instead of a coil spring, any other resilient means can be used to causethe piston to move towards the exit end of the device.

The modified piston of example 3 can be included in the configurationsof examples 1 or 2 so that the device has a dump dose and an exit doseas well as the sustained release payload within the body of the capsule,generally as described in Example 4.

Although it is preferable that the dump dose, the sustained releasepayload, and the exit dose are formulated differently, it is alsopossible that this configuration could be used to deliver a longerduration sustained release payload by including a sustained releaseportion in the dump dose, the main payload itself within the capsule,and also in the cavity within the piston, or some sub-combination ofthese three possibilities.

Although the four embodiments are described with reference to foldablewings, other forms of protrusions or means for retaining the capsulewithin the rumen can be used.

Field Study

In order to test the efficacy of the invention a field study wasperformed in respect of an embodiment of the invention comprising aplasticised starch overcap fitted to a sustained release capsule forsheep, the overcap comprising a dump dose of medicament. This was asingle dose, controlled total worm count efficacy study in which thedump dose medicament contained within the overcap on the capsulecomprised a combination of abamectin and levamisole, while the sustainedrelease medicament contained within the body of the capsule comprised acombination of abamectin and albendazole designed to be released over aperiod of 100 days.

An untreated control group, a group treated with an empty capsule fittedwith the overcap comprising the dump dose only, and a group treated witha standard abamectin/albendazole sustained release capsule were alsoincluded in the study.

Four days prior to treatment, a group of 30 sheep suspected ofharbouring a burden of gastrointestinal parasites and weighing between60 kg-80 kg were selected from a larger mob, ear tagged and faecalsampled for faecal egg count (FEC). From this mob of sheep, 24 animalswith positive FEC were selected for inclusion in the study. Animals wereintroduced to a diet of lucerne chaffage whilst on pasture.

On Day 0 the study animals were removed from pasture, weighed andrandomly assigned to 4 groups of n=6 based on individual bodyweight. Allanimals were faecal sampled for FEC and larval culture and thetreatments were administered to animals in Groups 1-3; while Group 4remained untreated. Animals were retained off pasture for the durationof the study. Treatment groups were:

-   -   Group 1: Abamectin/albendazole sustained release capsule        including an overcap comprising a dump dose of medicament        containing abamectin and levamisole    -   Group 2: Empty sustained release capsule with an overcap        comprising a dump dose of medicament containing abamectin and        levamisole    -   Group 3: Abamectin/albendazole sustained release capsule with no        dump dose overcap    -   Group 4: Untreated control

Ten days after treatment, all study animals were faecal sampled for FECto demonstrate faecal egg count reduction and confirm control group wormburdens. A larval culture was performed on pooled faeces from Group 4.The following day, all animals were necropsied and the abomasa, smalland large intestines were collected for total worm counts. Individualcapsules were recovered from treated animals in Groups 1 and 3 andmeasured to determine release kinetics. Capsules fitted with the overcapcontaining the dump dose of medicament (Groups 1 and 2) were examined toensure the housing and tablet had detached correctly.

Results Performance of the Overcap Containing the Dump Dose ofMedicament

Performance of the overcap containing the dump dose of medicament wasmeasured by the ability of the actives in the overcap(abamectin/levamisole) to reduce worm burdens in the animals. This wasprincipally demonstrated by comparing the result from Group 2 with theother treatment Groups.

Total worm counts: Mean total worm count results are shown in Tables 1a,1b and 1c. The control group harboured a mixed burden ofgastrointestinal nematodes, evident from the total worm count results.

TABLE 1a Arithmetic and geometric mean total worm counts - AbomasumSpecies Ostertagia/ Haemonchus contortus Teladorsagia spp.Trichostrongylus axei Stage Adult Immature Adult Immature Adult ImmatureArithmetic means Group 1 0.0   0.0   0.0   0.0   0.0   0.0   Group 20.0   0.0   16.7   0.0   0.0   0.0   Group 3 0.0   0.0   0.0   0.0  0.0   0.0   Group 4 50.0   8.3   1108.3    16.7   3850.0    0.0  Geometric means Group 1 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0^(a) Group 2 0.0 ^(a) 0.0 ^(a) 2.7 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) Group3 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) Group 4 8.6 ^(b)0.9 ^(a) 614.2 ^(b)    1.2 ^(a) 2943.6 ^(b)     0.0 ^(a) ^(a, b)Subscripts within the same column are not significantly different at p <0.05

TABLE 1b Arithmetic and geometric mean total worm counts - Smallintestine Species Trichostrongylus Nematodirus spp. spp. Cooperia spp.Stage Adult Immature Adult Immature Adult Immature Arithmetic meansGroup 1 0.0   0.0   0.0   0.0   0.0   0.0   Group 2 0.0   0.0   0.0  0.0   0.0   0.0   Group 3 0.0   0.0   0.0   0.0   0.0   0.0   Group 4366.7    100.0    1750.0    8.3   508.6    0.0   Geometric means Group 10.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) Group 2 0.0 ^(a)0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) Group 3 0.0 ^(a) 0.0 ^(a)0.0 ^(a) 0.0 ^(a) 0.0 ^(a) 0.0 ^(a) Group 4 93.1 ^(b)    49.1 ^(b)   1582.2 ^(b)     0.9 ^(a) 22.3 ^(b)    0.0 ^(a) ^(a b) Subscripts withinthe same column are not significantly different at p < 0.05

TABLE 1c Arithmetic and geometric mean total worm counts - Largeintestine Species Oesophagostomum Chabertia Trichuris spp. spp. spp.Stage Adult Adult Adult Arithmetic means Group 1 0.0 0.0   0.0 Group 20.0 0.0   0.0 Group 3 0.0 0.0   0.0 Group 4 43.3  6.7   23.3  Geometricmeans Group 1   0.0 ^(a) 0.0 ^(a)   0.0 ^(a) Group 2   0.0 ^(a) 0.0 ^(a)  0.0 ^(a) Group 3   0.0 ^(a) 0.0 ^(a)   0.0 ^(a) Group 4  31.1 ^(b) 2.7^(b)  20.5 ^(b) ^(a) ^(b) Subscripts within the same column are notsignificantly different at p < 0.05Percent efficacy (% E) for each group was calculated for each of theworm species (WS) present, using the following formula:

${\% \mspace{14mu} E} = {\frac{\begin{matrix}{{{Mean}\mspace{14mu} {of}\mspace{14mu} ({WS})\mspace{14mu} {in}\mspace{14mu} {controls}} -} \\{{mean}\mspace{14mu} {of}\mspace{14mu} ({WS})\mspace{14mu} {in}\mspace{14mu} {treated}\mspace{14mu} {group}}\end{matrix}}{{Mean}\mspace{14mu} {of}\mspace{14mu} ({WS})\mspace{14mu} {in}\mspace{14mu} {controls}} \times 100}$

Percentage efficacies calculated on total worm counts using botharithmetic and geometric means are shown in Table 2a, 2b and 2c.

TABLE 2a Percentage efficacies (by genus, based on abomasa Total WormCounts) Haemonchus Ostertagia/Teladorsagia Trichostrongylus contortusspp axei % Arithmetic Efficacy Group 1 100 100 100 Group 2 100 98.5 100Group 3 100 100 100 % Geometric Efficacy Group 1 100 100 100 Group 2 10099.6 100 Group 3 100 100 100

TABLE 2b Percentage efficacies (by genus, based on small intestinalTotal Worm Counts) Nematodirus Nematodirus spp. TrichostrongylusCooperia spp. Adult Immature spp. spp. % Arithmetic Efficacy Group 1 100100 100 100 Group 2 100 100 100 100 Group 3 100 100 100 100 % GeometricEfficacy Group 1 100 100 100 100 Group 2 100 100 100 100 Group 3 100 100100 100

TABLE 2c Percentage efficacies (by genus, based on large intestinalTotal Worm Counts) Oesophagostomum Chabertia Trichuris spp. spp. spp. %Arithmetic Efficacy Group 1 100 100 100 Group 2 100 100 100 Group 3 100100 % Geometric Efficacy Group 1 100 100 100 Group 2 100 100 100 Group 3100 100 100Performance of the Sustained Release Medicament within Capsule Body

To ensure that the overcap comprising the dump dose of medicament had noeffect on the payout of the sustained release portion of the device, thelinear payout of the tablet stack within the device having the dump doseovercap fitted

(Group 1) was compared with the linear payout of that from a standarddevice having no dump dose portion fitted (Group 3). The result was thatthe mean linear payout for Groups 1 and 3 was 7.85 and 7.91 mmrespectively, eleven days after administration. It can therefore beconcluded that the overcap quickly detached from the sustained releasecapsule and that the addition of the dump dose cap element to thesustained release device had no effect on the subsequent linear payoutwhen compared to the standard device, p=0.87.

1. A sustained release capsule comprising a hollow tubular body sealed at a first end, a movable piston within the body, a spring biasing the piston towards a second end of the body, an apertured cover at the second end to define a first chamber between the movable piston and the apertured cover capable of containing a first dose of material within the hollow tubular body for subsequent sustained release through the apertured cover into the rumen of an animal, wherein an overcap is releasably attached to the device at one end thereof to form a void between an end of the device and the overcap capable of containing a second dose of material within the void so that in use the second dose of material is delivered to the rumen when the overcap is breached or detaches from the device.
 2. A sustained release capsule as claimed in claim 1, wherein the overcap is attached to the second end of the device to form a void between the apertured cover and the overcap capable of containing the second dose of material within the void so that in use the second dose of material is delivered to the rumen when the overcap is breached or detaches from the second end of the device.
 3. A sustained release capsule comprising a hollow tubular body sealed at a first end, a movable piston within the body, a spring biasing the piston towards a second end of the body, an apertured cover at the second end to define a first chamber between the movable piston and the apertured cover capable of containing a first dose of material within the hollow tubular body for subsequent sustained release through the apertured cover into the rumen of an animal, wherein the movable piston has an end face facing towards the first dose, a hollow central sleeve extending rearwardly from the end face to assist in locating a spring, an aperture in the end face into the hollow interior of the central sleeve, the central sleeve having a closed portion distal from the end face to create a void capable of containing an exit dose of material.
 4. A sustained release capsule as claimed in claim 3, wherein the capsule further includes an overcap which is releasably attached to the second end to form a void between the apertured cover and the overcap capable of containing a second dose of material within the void so that in use the second dose of material is delivered to the rumen when the overcap is breached or detaches from the second end.
 5. A sustained release capsule as claimed in any one of claims 1, 2 or 4, wherein the overcap is releasably attached to the device by a dissolvable attachment.
 6. A sustained release capsule as claimed in any one of claims 1, 2, 4 or 5, wherein the overcap is made of a material which will dissolve or breakup in the rumen.
 7. A sustained release capsule as claimed in any one of claims 1, 2, 4, 5 or 6, wherein the overcap is made of a material selected from the group comprising cellulosic fibre, cardboard, paper, a water soluble plastics material and starch.
 8. A sustained release capsule as claimed in any one of the preceding claims, wherein the body has at least one external protrusion adapted in use to assist in retaining the capsule in the rumen of an animal.
 9. A sustained release capsule as claimed in claim 8, wherein the at least one protrusion consists of a pair of foldable wings.
 10. A sustained release capsule as claimed in any one of the preceding claims wherein the capsule is loaded with a first dose of material.
 11. A sustained release capsule as claimed in any one of claims 1, 2 and 4-10, wherein the capsule is loaded with a second dose of material in the overcap.
 12. A sustained release capsule as claimed in any one of claims 3-11, wherein the capsule is loaded with an exit dose of material.
 13. A sustained release capsule as claimed in claim 11, wherein the second dose of material in the overcap comprises copper needles. 